Routine Use of Maintenance Therapy in Follicular Lymphoma: Examine the Rationale for Maintenance Use Before Uniformly Adopting a Strategy

Follicular lymphoma (FL) is the second most frequently occurring lymphoma in the Western world, accounting for about 22% of B-cell lymphomas.[1,2] Although FL is generally an indolent-behaving cancer that responds to many agents, it exhibits a continuous pattern of relapses characterized by decreasing sensitivity to treatment over time.[3] Maintenance therapy has been used routinely for FL in clinical practice. The patterns of rituximab (R) maintenance use, patient characteristics associated with R-maintenance, and results regarding the effectiveness of maintenance from the National LymphoCare Study (NLCS)[4] were recently reported by Dr. Nastoupil.[5] In this prospective, observational study, among the 1,439 patients with FL who were treated with R-based induction therapy, 541 received R-maintenance. Initial treatment and maintenance or observation decisions were made by the treating physician. R-maintenance use following R-based induction was surprisingly frequent, given that these patients were treated before results of the studies of R-maintenance following initial R-based chemotherapy or single-agent R became available.[6-8] In the NLCS, R-maintenance occurred more commonly in patients with FL grade 1/2 and stage III/IV disease, in those treated in a region other than the Western United States, and in those treated in community practice. While R-maintenance use is commonplace, the factors listed here do not designate characteristics of patients more likely to need maintenance therapy or benefit from R-maintenance. The rationale for maintenance use and the identified benefits of R-maintenance in randomized trials need to be carefully examined before maintenance is uniformly utilized in patients with FL.

Treatment goals for patients with indolent lymphomas include improving overall survival (OS), sustaining disease control over a period of many years, reducing the risk of transformation to a more aggressive lymphoma, limiting treatment toxicity, prolonging the treatment-free interval, and improving quality of life.[9-11] Use of maintenance therapy in FL should be targeted to achieve one or more of these endpoints and avoid adversely impacting others. While definitions of FL maintenance therapy in clinical trials and clinical practice have been somewhat variable, ideally maintenance therapy would be limited to patients in complete remission or with minimal residual disease following initial therapy, and targeted toward improving OS and quality of life.[12] Clinical practice has altered this definition to focus on therapy that is of reduced intensity following a circumscribed induction regimen for initial therapy or relapsed disease. The advantage of this definition is that more patients are eligible for maintenance therapy, but this approach is hampered by differing magnitudes of induction response (complete response vs partial response vs stable disease), and these differences may cloud the benefit of R-maintenance for a specific population. Before maintenance therapy can be uniformly recommended to FL populations, clarification is needed regarding the differences between planned, serial interval retreatment (for patients with stable disease or partial remission) vs maintenance (for patients in remission with no detectable disease). Although these strategies may employ the same therapy, they often target different endpoints. Current studies utilize a general agreement that maintenance therapy is any therapy that follows induction therapy in patients with some level of response or stable disease, and this practical definition forms a common base upon which trials are compared; however, it has the previously noted drawbacks.

Current studies in FL have demonstrated that R-maintenance produces benefits in progression-free survival (PFS) in front-line treatment following R-chemotherapy[7] and single-agent R therapy,[6] and more detailed reviews are available addressing studies of R-maintenance in relapsed FL.[11-14] To date, prospective randomized studies have not shown consistent improvements in the other endpoints of interest previously noted. In addition, there are now a number of emerging oral agents (eg, ABT-199, ibrutinib, idelalisib, lenalidomide) and other antibody therapies (eg, nivolumab, obinutuzumab, ofatumumab) that have limited toxicity and are available commercially or in clinical trials for relapsed FL. This growing list of agents offers numerous possibilities for treatment of relapse, such that the added benefits of R-maintenance in prolonging both PFS and time to next treatment may not be worth the added time required for patients to receive treatment, the toxicity of treatment, and the cost of therapy. Moreover, the issues described will need to be readdressed, as each of these agents is evaluated in future maintenance strategies.

Financial Disclosure: Dr. Flowers is an unpaid consultant for Genentech for service on the LymphoCare Scientific Advisory Board and for Celgene for service on the CONNECT CLL Scientific Advisory Board. He reports research support from AbbVie, Acerta, Celgene, Genentech, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Millennium/Takeda, Onyx Pharmaceuticals, Pharmacyclics, and Spectrum and consulting fees from OptumRx and Seattle Genetics for work performed outside of the current commentary.

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